Submissions for variant NM_000329.3(RPE65):c.858+1G>T

dbSNP: rs61752899

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001270786	SCV001451547	pathogenic	Leber congenital amaurosis 2	2019-02-07	criteria provided, single submitter	clinical testing	The RPE65 c.858+1G>T variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.858+1G>T variant has been reported in three studies in which it was found in three probands diagnosed with Leber congenital amaurosis; two probands carried the variant in the homozygous state, the third individual was compound heterozygous for the c.858+1G>T and a second missense variant (Gu et al. 1997; Seong et al. 2008; Srilekha et al. 2015). The c.858+1G>T variant was reported to segregate with disease in an autosomal recessive manner in two consanguineous families of Indian descent. Individuals homozygous for the c.858+1G>T variant in these families showed an early onset and severe disease course, with a fundal appearance typical of retinitis pigmentosa. The c.858+1G>T variant was absent from 430 control subjects and is not found in the Genome Aggregation Database, in a region of good sequence coverage, and hence is presumed to be rare. Based on the available evidence, the c.858+1G>T variant is classified as pathogenic for Leber congenital amaurosis.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513924	SCV003523321	pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2022-05-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 98893). This variant is also known as c.912+1G>T. Disruption of this splice site has been observed in individual(s) with autosomal recessive RPE65-related conditions (PMID: 9326941, 18682808, 26147992). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 8 of the RPE65 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RPE65 are known to be pathogenic (PMID: 9326941, 9501220, 9843205, 18632300).
Retina International	RCV000085224	SCV000117361	not provided	not provided		no assertion provided	not provided